Relationship between fat-free mass and metabolic syndrome is shaped by ectopic fat in a UK Biobank cohort

Fat-free mass (FFM) is frequently interpreted as a surrogate to skeletal muscle, a key determinant of insulin sensitivity. Recent studies, however, reported that higher FFM is associated with greater insulin resistance suggesting that additional biological factors may confound its metabolic implications.

To determine whether visceral adipose tissue (VAT), muscle fat infiltration (MFI), and circulating sex hormones modify the associations between FFM and adverse metabolic outcomes.

Cross-sectional analysis of UK Biobank cohort recruited between 2006-2010.

59,269 individuals who had body composition measurements assessed by both dual-energy x-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) were included.

Prevalence of metabolic syndrome (MetS) and elevated glycated hemoglobin (HbA1c), evaluated across tertiles of total FFM, FFM adjusted to height2 (FFM/height2), and FFM relative to body weight (FFM/Wt). Effect modification by VAT, MFI, testosterone, sex hormone-binding globulin, and estradiol was assessed using moderation analyses.

Prevalence of MetS and elevated HbA1c increased across tertiles of total FFM, FFM/height2, whereas higher FFM/Wt was associated with lower prevalence of both outcomes. VAT exerted the strongest influence on FFM-metabolic outcome associations. MFI modified associations of total FFM and FFM/height2 with adverse metabolic outcomes, although some effects were attenuated after adjusting for VAT. Sex hormones showed modest, metric-specific modifying effects.

Our findings show that the adverse metabolic outcomes associated with FFM are not inherent to FFM itself but are heavily shaped by visceral adiposity, muscle composition, and the specific FFM metric.